Intraoral administration of medicaments has been carried out according to the prior art. See U.S. Pat. No. 4,229,447 to PORTER. This patent discloses the intraoral administration of benzodiazepines including diazepam, lorazepam, oxazapam, temazapam, and chlordiazepoxide. According to Porter it is known in the art to administer benzodiazapines either orally or parenterally (i.e. by injection), especially intramuscularly or subcutaneously. Administering benzodiazepines by injection enables rapid attainment of effective plasma concentrations, that is more rapid than the plasma concentrations obtained following oral administration. One advantage of the intraoral administration as opposed to parenteral administration is that there is no injection site where pain and inflammation may develop. Another such advantage is that intraoral administration does not require sterilization of the preparations and the hypodermic syringes. Furthermore, in many situations self-administration of a medicament by parenteral means is not possible for a patient.
In U.S. Patent 5,739,136 to Ellinwood Jr. et al the medicament selected for intraoral administration is one that if given by oral administration is metabolized to an unwanted or aversive metabolite that is increasingly formed during gastrointestinal tract absorption and subsequent portal vein transport into the liver. Examples of such medicaments include not only the benzodiazepines especially a trifluorobenzodiazepine such as quazepam, but also other medicaments where it is advantageous to avoid first-pass metabolism such as the antianxiety/anticonvulsant/antihypnotic agents propoxyphene, nefazodone, trazodone, clomipramine, bupropion and combinations thereof. Unlike Porter, Ellinwood Jr. et al is not only concerned with rapidly attaining effective plasma concentrations of the intraorally administered medicament, but is especially concerned that the medicament include a drug where first pass-metabolism is to be avoided. The intraoral administration of the antianxiety/anticonvulsant/antihypnotic agents decreases the metabolism to the undesired metabolites.
In U.S. Pat. No. 6,183,778 to Jagotec A G, et al. the patent describes a multiple layer tablet capable of liberating one or more drugs at different release rates. This multi-layer dosage form is intended solely for oral administration and therefore must undergo first pass metabolism. Although it contains multiple releasing layers there is no dosage mechanism to provide the advantages presented by intraoral administration.
Remingtons, The Science and Practice of Pharmacy, 20th Ed., contains a complete history of dosage forms, including compressed tablets and triturate tablets; therefore, in the present invention no novelty is claimed in the broad practice of producing compressed tablets from dry powder or granulation or triturate tablets molded from a semi-wet powder. The uniqueness of the composition of this invention resides in its ability to provide in one dosage form the best features of both the compressed tablet and the triturate tablet.
The unique features of compressed tablets are well known in the art and is the dosage form most commonly employed as the method of choice for oral administration through which the tablets are digested and the drug absorbed into systemic circulation. Compressed tablets are not fragile and can withstand substantial handling without chipping or cracking. The compressed tablets can be formulated to provide disintegration and or dissolution of the active(s) at a specified time range after ingestion. They can be chewed but when used in this manner the tablets may lose some of their versatility. Compressed tablets can also be coated with a mixture containing a drug which will dissolve before the bulk of the tablet and may be absorbed intraorally. Compressed tablets may be layered, with one or more layers formulated to give early and rapid dissolution of drug in those layers as well as sustained dissolution of drugs in those layers. Compressed tablets may contain beads that are made of drugs in sustained-release or delayed-release forms in the tablet matrix.
Normally compressed tablets are uniformly solid but in this invention by employing tooling with a core rod, a ring shaped or annular tablet is produced, commonly referred to as a compressed annular tablet (CAT). Compressed tablets generally are intended to remain intact and not disintegrate until they reach the stomach or intestine. Compressed tablets are generally formulated with appropriate diluents or binders and/or polymers or waxes to obtain a desired appropriate hardness and are formulated as immediate, sustained or delayed released tablets.
Molded tablet triturates are, on the other hand, less versatile than compressed tablets. Tablet triturates usually are made from moist material comprising mainly one or more water soluble sugars. After the moist mass is incorporated in the mold to form a tablet triturate, the wet tablet triturates are ejected and dried. The resulting tablet triturates are generally more porous than the compressed tablets. Their main advantage is being rapidly disintegradable and soluble or dispersible in salivary fluid. They therefore lend themselves to intraoral administration and the avoidance of first pass metabolism. Triturate tablets have been more characterized by the disadvantages of friability or softness and thus require careful handling to prevent chipping and breaking particularly on their edges. In the present invention this disadvantage is overcome by molding and hence protecting the triturate tablet within center cavity of the compressed annular tablet, thereby eliminating the friability of the triturate while retaining the advantage of a rapidly soluble triturate tablet.
Nowhere in the literature is there a preparation of a triturate tablet which is molded within a compressed annular tablet.
Nowhere in the prior art references is there a disclosure of a pharmaceutical composition of a compressed annular tablet with a molded tablet triturate that effectively administers a therapeutically effective amount of pharmaceutically active ingredients by both intraoral means to obtain a rapid onset of desired therapeutic effect via plasma concentration and by oral means to obtain a more sustaining as well as complementary therapeutic effect.